Novel protein kinase targets in vascular smooth muscle therapeutics

Abstract

Many signaling factors have been identified over the years that serve as mechanistic foundations for the pathogenesis and/or maintenance of cardiovascular disease (CVD). Of these, cyclic nucleotide-driven protein kinases in vascular smooth muscle (VSM) are of essential importance. Comprised primarily of cyclic AMP-dependent and cyclic GMP-dependent protein kinases, these ubiquitous signaling molecules have capacity to operate through numerous downstream effectors including vasodilator-stimulated phosphoprotein (VASP) to control aberrant VSM growth elemental to CVD. As more information is gathered regarding genetic, biochemical, molecular and cellular makeup of CVD including VSM cyclic nucleotide-dependent protein kinases and VASP, advances will be made in precision medicine by identifying more precise therapeutic targets to enhance clinical decision making.

Figure. Cyclic nucleotide-mediated, protein kinase-driven VASP as a target for precision medicine in vascular smooth muscle

The ubiquitous cyclic purine nucleotides cyclic AMP and cyclic GMP activate their predominant Ser/Thr kinases PKA and PKG, respectively, which target numerous effectors including focal adhesion cytoskeletal vasodilator-stimulated phosphoprotein (VASP) in vascular smooth muscle (VSM). VASP can operate to normalize underlying mechanisms of VSM pathology including aberrant cell proliferation and migration, altered extracellular matrix balance, and enhanced apoptosis, making it an attractive target for therapeutic intervention. Recent observations from our lab [18] also lend credence for positive feedback of VASP on upstream PKG activity in VSM. PKA and PKG as upstream activators and VASP as perhaps a more selective downstream target all hold promise for precision medicine in VSM in the context of cardiovascular disorders.